DESCRIPTION (provided by applicant: Chronic lymphocytic leukemia (CLL) is the most prevalent hematologic cancer in the US. Importantly, and in contrast with other hematologic malignancies, CLL responds only transiently to chemotherapy and there is no available curative therapy. Activating mutations in NOTCH1 have been recently found in 10-15% of CLL cases and are associated with poor prognosis, disease progression, chemotherapy resistance and transformation to diffuse large B cell lymphoma (DLBCL) (Fabbri et al., J Exp Med 2011; Puente et al, Nature 2011). Notably, NOTCH1 signaling can be effectively blocked with inhibitory antibodies and gamma-secretase inhibitors, currently under development as anti-NOTCH therapies for the treatment of cancer. Our central hypothesis is that NOTCH1 mutations may contribute to the pathogenesis of CLL by disrupting specific transcriptional programs that regulate cell proliferation, differentiation and survival in CLL cells. The goals of this research proposal are to define the molecular and cellular functions of NOTCH1 in CLL transformation, to analyze the oncogenic effects of mutant NOTCH1 in vivo, and to test the effects of NOTCH inhibition alone and in combination with chemotherapy in the treatment of CLL.